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Characterization of human plasma-derived exosomal RNAs by deep sequencing.

Huang, Xiaoyi, Yuan, Tiezheng, Tschannen, Michael, Sun, Zhifu, Jacob, Howard, Du, Meijun, Liang, Meihua, Dittmar, Rachel L, Liu, Yong, Liang, Mingyu, Kohli, Manish, Thibodeau, Stephen N, Boardman, Lisa, Wang, Liang·2013·BMC Genomics
DOI 10.1186/1471-2164-14-319PMC PMC3653748
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Abstract

Background: Exosomes, endosome-derived membrane microvesicles, contain specific RNA transcripts that are thought to be involved in cell-cell communication. These RNA transcripts have great potential as disease biomarkers. To characterize exosomal RNA profiles systemically, we performed RNA sequencing analysis using three human plasma samples and evaluated the efficacies of small RNA library preparation protocols from three manufacturers. In all we evaluated 14 libraries (7 replicates). Results: From the 14 size-selected sequencing libraries, we obtained a total of 101.8 million raw single-end reads, an average of about 7.27 million reads per library. Sequence analysis showed that there was a diverse collection of the exosomal RNA species among which microRNAs (miRNAs) were the most abundant, making up over 42.32% of all raw reads and 76.20% of all mappable reads. At the current read depth, 593 miRNAs were detectable. The five most common miRNAs (miR-99a-5p, miR-128, miR-124-3p, miR-22-3p, and miR-99b-5p) collectively accounted for 48.99% of all mappable miRNA sequences. MiRNA target gene enrichment analysis suggested that the highly abundant miRNAs may play an important role in biological functions such as protein phosphorylation, RNA splicing, chromosomal abnormality, and angiogenesis. From the unknown RNA sequences, we predicted 185 potential miRNA candidates. Furthermore, we detected significant fractions of other RNA species including ribosomal RNA (9.16% of all mappable counts), long non-coding RNA (3.36%), piwi-interacting RNA (1.31%), transfer RNA (1.24%), small nuclear RNA (0.18%), and small nucleolar RNA (0.01%); fragments of coding sequence (1.36%), 5′ untranslated region (0.21%), and 3′ untranslated region (0.54%) were also present. In addition to the RNA composition of the libraries, we found that the three tested commercial kits generated a sufficient number of DNA fragments for sequencing but each had significant bias toward capturing specific RNAs. Conclusions: This study demonstrated that a wide variety of RNA species are embedded in the circulating vesicles. To our knowledge, this is the first report that applied deep sequencing to discover and characterize profiles of plasma-derived exosomal RNAs. Further characterization of these extracellular RNAs in diverse human populations will provide reference profiles and open new doors for the development of blood-based biomarkers for human diseases.

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  1. Mears R, Craven RA, Hanrahan S, Totty N, Upton C, Young SL, Patel P, Selby PJ, Banks RE: Proteomic analysis of melanoma-derived exosomes by two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. Proteomics. 2004, 4 (12): 4019-4031. 10.1002/pmic.200400876. · DOI
  2. Vlassov AV, Magdaleno S, Setterquist R, Conrad R: Exosomes: Current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta. 2012, 1820: 940-948. 10.1016/j.bbagen.2012.03.017. · DOI
  3. Thery C, Ostrowski M, Segura E: Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009, 9 (8): 581-593. 10.1038/nri2567. · DOI
  4. van Niel G, Porto-Carreiro I, Simoes S, Raposo G: Exosomes: a common pathway for a specialized function. J Biochem. 2006, 140 (1): 13-21. 10.1093/jb/mvj128. · DOI
  5. Pegtel DM, van de Garde MD, Middeldorp JM: Viral miRNAs exploiting the endosomal-exosomal pathway for intercellular cross-talk and immune evasion. Biochim Biophys Acta. 2011, 1809 (11–12): 715-721. · DOI
  6. Taylor DD, Gercel-Taylor C: MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 2008, 110 (1): 13-21. 10.1016/j.ygyno.2008.04.033. · DOI
  7. Mittelbrunn M, Gutierrez-Vazquez C, Villarroya-Beltri C, Gonzalez S, Sanchez-Cabo F, Gonzalez MA, Bernad A, Sanchez-Madrid F: Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun. 2011, 2: 282- · DOI
  8. Rabinowits G, Gercel-Taylor C, Day JM, Taylor DD, Kloecker GH: Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer. 2009, 10 (1): 42-46. 10.3816/CLC.2009.n.006. · DOI
  9. Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT, Carter BS, Krichevsky AM, Breakefield XO: Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008, 10 (12): 1470-1476. 10.1038/ncb1800. · DOI · Paper page
  10. Johansson SM, Admyre C, Rahman QK, Filen JJ, Lahesmaa R, Norman M, Neve E, Scheynius A, Gabrielsson S: Exosome-like vesicles in human breast milk. J Immunol. 2006, 176: S184-S184.
  11. Gatti JL, Metayer S, Belghazi M, Dacheux F, Dacheux JL: Identification, proteomic profiling, and origin of ram epididymal fluid exosome-like vesicles. Biol Reprod. 2005, 72 (6): 1452-1465. 10.1095/biolreprod.104.036426. · DOI
  12. Harada H, Mitsuhashi M: Assessment of Post-Transplant Kidney Function by Measuring Glomerulus- and Tubule-Specific mRNAs in Urine Exosome. Am J Transplant. 2012, 12: 369-370. 10.1111/j.1600-6143.2011.03888.x. · DOI
  13. Ben-Dov IZ, Brown M, Whalen VM, Tuschl T: Profiling Urine Cell and Exosome Microrna Using a Barcoded Small Rna Deep Sequencing Approach. Am J Kidney Dis. 2011, 57 (4): A24-A24. · DOI
  14. Conde-Vancells J, Rodriguez-Suarez E, Gonzalez E, Berisa A, Gil D, Embade N, Valle M, Luka Z, Elortza F, Wagner C: Candidate biomarkers in exosome-like vesicles purified from rat and mouse urine samples. Proteom Clin Appl. 2010, 4 (4): 416-425. 10.1002/prca.200900103. · DOI
  15. Blanc L, De Gassart A, Geminard C, Bette-Bobillo P, Vidal M: Exosome release by reticulocytes - An integral part of the red blood cell differentiation system. Blood Cell Mol Dis. 2005, 35 (1): 21-26. 10.1016/j.bcmd.2005.04.008. · DOI
  16. Jones JC, Knox SJ: Serum Exosome Biomarkers for Immunotherapy and Radiation Responses. Int J Radiat Oncol. 2011, 81 (2): S754-S755. · DOI
  17. Alge JL, Janech M, Schwacke J, Arthur J, Costa LJ: Proteomic Analysis of Plasma Exosome-Associated Proteins Reveals That Differences In Kappa: Lambda Ratios Predict Severe Acute Graft-Versus-Host Disease Early After Allogeneic Hematopoietic Stem Cell Transplantation. Blood. 2010, 116 (21): 547-547. · DOI
  18. Looze C, Yui D, Leung L, Ingham M, Kaler M, Yao XL, Wu WW, Shen RF, Daniels MP, Levine SJ: Proteomic profiling of human plasma exosomes identifies PPAR gamma as an exosome-associated protein. Biochem Biophys Res Commun. 2009, 378 (3): 433-438. 10.1016/j.bbrc.2008.11.050. · DOI
  19. Zhang J, Hawari FI, Shamburek RD, Adamik B, Kaler M, Islam A, Liao DW, Rouhani FN, Ingham M, Levine SJ: Circulating TNFR1 exosome-like vesicles partition with the LDL fraction of human plasma. Biochem Biophys Res Commun. 2008, 366 (2): 579-584. 10.1016/j.bbrc.2007.12.011. · DOI
  20. Paredes PT, Esser J, Admyre C, Nord M, Rahman QK, Lukic A, Radmark O, Gronneberg R, Grunewald J, Eklund A: Bronchoalveolar lavage fluid exosomes contribute to cytokine and leukotriene production in allergic asthma. Allergy. 2012, 67 (7): 911-919. 10.1111/j.1398-9995.2012.02835.x. · DOI
  21. Palanisamy V, Sharma S, Deshpande A, Zhou H, Gimzewski J, Wong DT: Nanostructural and Transcriptomic Analyses of Human Saliva Derived Exosome. PLoS One. 2010, 5 (1): e8577-10.1371/journal.pone.0008577. · DOI
  22. Peng P, Yan Y, Keng S: Exosomes in the ascites of ovarian cancer patients: Origin and effects on anti-tumor immunity. Oncol Rep. 2011, 25 (3): 749-762.
  23. Zhong HJ, Yang YS, Ma SL, Xiu FM, Cai ZJ, Zhao HG, Du LB: Induction of a tumour-specific CTL response by exosomes isolated from heat-treated malignant ascites of gastric cancer patients. Int J Hyperther. 2011, 27 (6): 604-611. 10.3109/02656736.2011.564598. · DOI
  24. Street JM, Barran PE, Mackay CL, Weidt S, Balmforth C, Walsh TS, Chalmers RTA, Webb DJ, Dear JW: Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J Transl Med. 2012, 10: 5-10.1186/1479-5876-10-5. · DOI
  25. Yu SH, Liu CR, Su KH, Wang JH, Liu YL, Zhang LM, Li CY, Cong YZ, Kimberly R, Grizzle WE: Tumor exosomes inhibit differentiation of bone marrow dendritic cells. J Immunol. 2007, 178 (11): 6867-6875. · DOI · Paper page
  26. Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan MLG, Karlsson JM, Baty CJ, Gibson GA, Erdos G, Wang ZL: Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood. 2012, 119 (3): 756-766. 10.1182/blood-2011-02-338004. · DOI · Paper page
  27. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar C: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012, 18 (6): 883-891. 10.1038/nm.2753. · DOI · Paper page
  28. Al-Mayah AH, Irons SL, Pink RC, Carter DR, Kadhim MA: Possible role of exosomes containing RNA in mediating nontargeted effect of ionizing radiation. Radiat Res. 2012, 177 (5): 539-545. 10.1667/RR2868.1. · DOI
  29. Kogure T, Lin WL, Yan IK, Braconi C, Patel T: Intercellular Nanovesicle-Mediated microRNA Transfer: A Mechanism of Environmental Modulation of Hepatocellular Cancer Cell Growth. Hepatology. 2011, 54 (4): 1237-1248. 10.1002/hep.24504. · DOI · Paper page
  30. Liu YL, Xiang XY, Zhuang XY, Zhang SY, Liu CR, Cheng ZQ, Michalek S, Grizzle W, Zhang HG: Contribution of MyD88 to the Tumor Exosome-Mediated Induction of Myeloid Derived Suppressor Cells. Am J Pathol. 2010, 176 (5): 2490-2499. 10.2353/ajpath.2010.090777. · DOI
  31. Ohshima K, Inoue K, Fujiwara A, Hatakeyama K, Kanto K, Watanabe Y, Muramatsu K, Fukuda Y, Ogura S, Yamaguchi K: Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS One. 2010, 5 (10): e13247-10.1371/journal.pone.0013247. · DOI
  32. Schorey JS, Bhatnagar S: Exosome function: From tumor immunology to pathogen biology. Traffic. 2008, 9 (6): 871-881. 10.1111/j.1600-0854.2008.00734.x. · DOI
  33. Michael A, Bajracharya SD, Yuen PST, Zhou H, Star RA, Illei GG, Alevizos I: Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis. 2010, 16 (1): 34-38. 10.1111/j.1601-0825.2009.01604.x. · DOI
  34. Ciesla M, Skrzypek K, Kozakowska M, Loboda A, Jozkowicz A, Dulak J: MicroRNAs as biomarkers of disease onset. Anal Bioanal Chem. 2011, 401 (7): 2051-2061. 10.1007/s00216-011-5001-8. · DOI
  35. Wittmann J, Jack HM: Serum microRNAs as powerful cancer biomarkers. Bba-Rev Cancer. 2010, 1806 (2): 200-207.
  36. Bellingham SA, Coleman BM, Hill AF: Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells. Nucleic Acids Res. 2012, 40 (21): 10937-10949. 10.1093/nar/gks832. · DOI
  37. Rupp AK, Rupp C, Keller S, Brase JC, Ehehalt R, Fogel M, Moldenhauer G, Marme F, Sultmann H, Altevogt P: Loss of EpCAM expression in breast cancer derived serum exosomes: role of proteolytic cleavage. Gynecol Oncol. 2011, 122 (2): 437-446. 10.1016/j.ygyno.2011.04.035. · DOI
  38. Lance RS, Drake RR, Troyer DA: Multiple recognition assay reveals prostasomes as promising plasma biomarkers for prostate cancer. Expert Rev Anticanc. 2011, 11 (9): 1341-1343. 10.1586/era.11.134. · DOI
  39. Bryant RJ, Pawlowski T, Catto JW, Marsden G, Vessella RL, Rhees B, Kuslich C, Visakorpi T, Hamdy FC: Changes in circulating microRNA levels associated with prostate cancer. Br J Cancer. 2012, 106 (4): 768-774. 10.1038/bjc.2011.595. · DOI
  40. Zhang Y, Wiggins BE, Lawrence C, Petrick J, Ivashuta S, Heck G: Analysis of plant-derived miRNAs in animal small RNA datasets. BMC Genomics. 2012, 13: 381-10.1186/1471-2164-13-381. · DOI
  41. Warner MS, Geraghty RJ, Martinez WM, Montgomery RI, Whitbeck JC, Xu R, Eisenberg RJ, Cohen GH, Spear PG: A cell surface protein with herpesvirus entry activity (HveB) confers susceptibility to infection by mutants of herpes simplex virus type 1, herpes simplex virus type 2, and pseudorabies virus. Virology. 1998, 246 (1): 179-189. 10.1006/viro.1998.9218. · DOI
  42. Biederbick A, Rosser R, Storre J, Elsasser HP: The VSFASSQQ motif confers calcium sensitivity to the intracellular apyrase LALP70. BMC Biochem. 2004, 5: 8-10.1186/1471-2091-5-8. · DOI
  43. Smith JL, Kupchak BR, Garitaonandia I, Hoang LK, Maina AS, Regalla LM, Lyons TJ: Heterologous expression of human mPRalpha, mPRbeta and mPRgamma in yeast confirms their ability to function as membrane progesterone receptors. Steroids. 2008, 73 (11): 1160-1173. 10.1016/j.steroids.2008.05.003. · DOI
  44. Friedlander MR, Mackowiak SD, Li N, Chen W, Rajewsky N: miRDeep2 accurately identifies known and hundreds of novel microRNA genes in seven animal clades. Nucleic Acids Res. 2012, 40 (1): 37-52. 10.1093/nar/gkr688. · DOI · Paper page
  45. Thery C, Zitvogel L, Amigorena S: Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002, 2 (8): 569-579. · DOI
  46. Keller S, Ridinger J, Rupp AK, Janssen JWG, Altevogt P: Body fluid derived exosomes as a novel template for clinical diagnostics. J Transl Med. 2011, 9: 86-10.1186/1479-5876-9-86. · DOI
  47. Reid G, Kirschner MB, van Zandwijk N: Circulating microRNAs: Association with disease and potential use as biomarkers. Crit Rev Oncol Hematol. 2011, 80 (2): 193-208. 10.1016/j.critrevonc.2010.11.004. · DOI
  48. Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, Mitchell PS, Bennett CF, Pogosova-Agadjanyan EL, Stirewalt DL: Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci USA. 2011, 108 (12): 5003-5008. 10.1073/pnas.1019055108. · DOI · Paper page
  49. Gallo A, Tandon M, Alevizos I, Illei GG: The Majority of MicroRNAs Detectable in Serum and Saliva Is Concentrated in Exosomes. PLoS One. 2012, 7 (3): e30679-10.1371/journal.pone.0030679. · DOI · Paper page
  50. Eldh M, Lotvall J, Malmhall C, Ekstrom K: Importance of RNA isolation methods for analysis of exosomal RNA: evaluation of different methods. Mol Immunol. 2012, 50 (4): 278-286. 10.1016/j.molimm.2012.02.001. · DOI
  51. Nolte-'t Hoen EN, Buermans HP, Waasdorp M, Stoorvogel W, Wauben MH, t Hoen PA: Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions. Nucleic Acids Res. 2012, 40 (18): 9272-9285. 10.1093/nar/gks658. · DOI
  52. Sun D, Lee YS, Malhotra A, Kim HK, Matecic M, Evans C, Jensen RV, Moskaluk CA, Dutta A: miR-99 family of MicroRNAs suppresses the expression of prostate-specific antigen and prostate cancer cell proliferation. Cancer Res. 2011, 71 (4): 1313-1324. 10.1158/0008-5472.CAN-10-1031. · DOI
  53. Turcatel G, Rubin N, El-Hashash A, Warburton D: MIR-99a and MIR-99b modulate TGF-beta induced epithelial to mesenchymal plasticity in normal murine mammary gland cells. PLoS One. 2012, 7 (1): e31032-10.1371/journal.pone.0031032. · DOI
  54. Shi XB, Xue L, Ma AH, Tepper CG, Gandour-Edwards R, Kung HJ, Devere White RW: Tumor suppressive miR-124 targets androgen receptor and inhibits proliferation of prostate cancer cells. Oncogene. 2012, 10.1038/onc.2012.425. · DOI
  55. Lang Q, Ling C: MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA. Biochem Biophys Res Commun. 2012, 426 (2): 247-252. 10.1016/j.bbrc.2012.08.075. · DOI
  56. Xia J, Wu Z, Yu C, He W, Zheng H, He Y, Jian W, Chen L, Zhang L, Li W: miR-124 inhibits cell proliferation in gastric cancer through down-regulation of SPHK1. J Pathol. 2012, 227 (4): 470-480. 10.1002/path.4030. · DOI
  57. Lv XB, Jiao Y, Qing Y, Hu H, Cui X, Lin T, Song E, Yu F: miR-124 suppresses multiple steps of breast cancer metastasis by targeting a cohort of pro-metastatic genes in vitro. Chin J Cancer. 2011, 30 (12): 821-830. 10.5732/cjc.011.10289. · DOI
  58. Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, Vandenberg SR, Ginzinger DG, James CD, Costello JF: miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008, 6: 14-10.1186/1741-7015-6-14. · DOI · Paper page
  59. Huang TC, Chang HY, Chen CY, Wu PY, Lee H, Liao YF, Hsu WM, Huang HC, Juan HF: Silencing of miR-124 induces neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis through promoting AHR. FEBS Lett. 2011, 585 (22): 3582-3586. 10.1016/j.febslet.2011.10.025. · DOI
  60. Friedlander MR, Chen W, Adamidi C, Maaskola J, Einspanier R, Knespel S, Rajewsky N: Discovering microRNAs from deep sequencing data using miRDeep. Nat Biotechnol. 2008, 26 (4): 407-415. 10.1038/nbt1394. · DOI
  61. Cock PJ, Fields CJ, Goto N, Heuer ML, Rice PM: The Sanger FASTQ file format for sequences with quality scores, and the Solexa/Illumina FASTQ variants. Nucleic Acids Res. 2010, 38 (6): 1767-1771. 10.1093/nar/gkp1137. · DOI
  62. Kozomara A, Griffiths-Jones S: miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 2011, 39 (Database issue): 152-157. · DOI · Paper page
  63. Wang X: miRDB: a microRNA target prediction and functional annotation database with a wiki interface. RNA. 2008, 14 (6): 1012-1017. 10.1261/rna.965408. · DOI
  64. Wang X, El Naqa IM: Prediction of both conserved and nonconserved microRNA targets in animals. Bioinformatics (Oxford, England). 2008, 24 (3): 325-332. 10.1093/bioinformatics/btm595. · DOI
  65. da Huang W, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009, 4 (1): 44-57. · DOI · Paper page

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Metadata

Authors
Huang, X., Yuan, T., Tschannen, M., Sun, Z., Jacob, H., Du, M., Liang, M., Dittmar, R. L., Liu, Y., Liang, M., Kohli, M., Thibodeau, S. N., Boardman, L., & Wang, L.
Venue
BMC Genomics
Publisher
Springer Science and Business Media LLC
Published
2013-05-10
Volume
14
Issue
1
ISSN
1471-2164
DOI
10.1186/1471-2164-14-319
PMC
PMC3653748
Cited by
932
References
5
Language
en

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